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J Physiol Sci (2012) 62:163–172 DOI 10.1007/s12576-012-0196-9

REVIEW

Role of 15-/15-hydroxyeicosatetraenoic acid in hypoxia-induced pulmonary

Daling Zhu • Yajuan Ran

Received: 29 September 2011 / Accepted: 25 January 2012 / Published online: 14 February 2012 Ó The Physiological Society of Japan and Springer 2012

Abstract Pulmonary arterial hypertension (PAH) is a Introduction rare disease with a complex aetiology characterized by elevated pulmonary artery resistance, which leads to right (PH) is a severe and frequently heart ventricular afterload and ultimately progressing to fatal disease characterized by elevated mean pulmonary right ventricular failure and often death. In addition to arterial (PA) pressure greater than 25 mmHg at rest or other factors, metabolites of cascade play greater than 30 mmHg with exercise [1], and which con- an important role in the pulmonary vasculature, and dis- tributes to the morbidity and mortality of adult and pedi- ruption of signaling pathways of arachidonic acid plays a atric patients with various and heart diseases. central role in the pathogenesis of PAH. 15-Lipoxygenase According to the Venice Classification of Pulmonary (15-LO) is upregulated in pulmonary artery endothelial Hypertension in 2003, PH is currently classified into five cells and smooth muscle cells of PAH patients, and its categories as listed in Table 1. Importantly, many of these metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) in diseases or conditions are associated with persistent or particular seems to play a central role in the contractile intermittent hypoxia, either globally or regionally, within machinery, and in the initiation and propagation of cell confined areas of the lung [2]. The acute hypoxia-induced proliferation via its effects on signal pathways, mitogens, pulmonary (HPV) is an important mech- and cell cycle components. Here, we focus on our impor- anism that aids in matching ventilation with perfusion by tant research into the role played by 15-LO/15-HETE, directing blood flow from poorly ventilated regions of the which promotes a proliferative, antiapoptotic, and vaso- lung to areas with normal or relatively high ventilation. constrictive physiological milieu leading to hypoxic pul- Although acute HPV benefits gas exchange and maximizes monary hypertension. oxygenation of venous blood in the pulmonary artery, sustained HPV or chronic exposure to hypoxia is a major Keywords Hypoxic pulmonary hypertension Á cause for the elevated pulmonary vascular resistance and 15-Lipoxygenase Á 15-Hydroxyeicosatetraenoic acid Á pulmonary arterial remodeling (PAR) in patients with Vasoconstriction Á Remodeling pulmonary arterial hypertension (PAH) associated with hypoxic cardiopulmonary diseases [3]. Vascular remodel- ing is characterized largely by medial hypertrophy and hyperplasia due to enhanced vascular smooth muscle cell D. Zhu (&) (VSMC) proliferation or attenuated apoptosis and endo- College of Pharmacy, Harbin Medical University-Daqing, thelial cell over-proliferation [4, 5]. However, the mecha- No. 1 Xinyang Street, High-tech Zone, Daqing 163319, Heilongjiang, People’s Republic of China nism of pulmonary vascular remodeling (PVR) and e-mail: [email protected] pulmonary hypertension is still unknown. The arachidonic acid cascade plays a vital role in D. Zhu Á Y. Ran homeostasis of the endothelium and VSMCs, and has been Biopharmaceutical Key Laboratory of Heilongjiang Province, 157 Baojian Road, Nangang District, Harbin 150081, observed in dysregulation of downstream pathways of Heilongjiang, People’s Republic of China arachidonic acid in patients with PAH and in animal 123 164 J Physiol Sci (2012) 62:163–172

Table 1 Clinical classification of pulmonary hypertension models. More and more biological data suggest that ara- Venice Classification of Pulmonary Hypertension (2003) chidonic acid metabolites of (LOs) play pivotal roles in the pathological development of PAH. LOs 1. Pulmonary arterial hypertension (PAH) are a family of non-heme iron-containing which 1.1. Idiopathic (IPAH) dioxygenate polyunsaturated fatty acids to hydroperoxyl 1.2. Familial (FPAH) metabolites. As shown in Table 2, LOs mainly include 1.3. Associated with (APAH) four isoforms, 5-lipoxygenase (5-LO) [6], 8-lipoxygenase 1.3.1. Collagen vascular disease (8-LO) [7, 8], 12-lipoxygenase (12-LO) [9], and 1.3.2. Congenital systemic-to-pulmonary shunts 15-lipoxygenase (15-LO) [10], which correspond to the 1.3.3. Portal hypertension carbon position of arachidonic acid oxygenation, whereas 1.3.4. HIV infection 8-LO was not found to be expressed in human tissues. LOs 1.3.5. Drugs and toxins are involved in of vasoactive mediators, 1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher growth factors, adhesion molecules, and [10–12], disease, hereditary hemorrhagic telangiectasia, and hence are important targets for the atherogenesis, hemoglobinopathies, myeloproliferative disorders, splenectomy) vasoconstriction, and vascular remodeling. Moreover, 1.4. Associated with significant venous or capillary involvement LOs-derived compounds impact the metabolic character- 1.4.1. Pulmonary veno-occlusive disease (PVOD) istics of vascular cells, particularly those of endothelial 1.4.2. Pulmonary capillary hemangiomatosis (PCH) cells (EC) and smooth muscles cells (SMC) [13, 14]. In our 1.5. Persistent pulmonary hypertension of the newborn laboratory, we have reported that 15-LO/15-HETE played 2. Pulmonary hypertension with left heart disease an important role in hypoxic pulmonary hypertension 2.1. Left-sided atrial or ventricular heart disease (HPH). Therefore, this review is intended to provide a 2.2. Left-sided valvular heart disease comprehensive overview of the effect of 15-LO/15-HETE 3. Pulmonary hypertension associated with lung diseases and/or on HPH, and also to propose underlying the important hypoxemia aspects of 5-LO and 12-LO in PAH. 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disordered breathing Basic properties of LOs 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude Two distinct types of 15-LO have been identified in 3.6. Developmental abnormalities humans: reticulocyte type of 15-LO-1 [15] and epidermis 4. Pulmonary hypertension owing to chronic thrombotic and/or type of 15-LO-2 [16]. 15-LO-1 was initially discovered in a embolic disease rabbit reticulocytes mass at a 75-kD, single-polypeptide 4.1. Thromboembolic obstruction of proximal pulmonary arteries chain [17]; the has a two-domain structure [18] 4.2. Thromboembolic obstruction of distal pulmonary arteries with one non-heme iron per molecule. 15-LO-2 was sub- 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, sequently identified, and its expression has been reported in foreign material) human prostate, skin, and cornea [17]. Both enzymes con- 5. Miscellaneous: sarcoidosis, histiocytosis X, lymphangiomatosis, vert arachidonic acid to 15-hydroperoxyeicosatetraenoic compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) acid (15(S)-HPETE). 15(S)-HPETE is unstable and can be reduced by to the corresponding

Table 2 Basic properties of LOs Gene name Alternative nomenclature Predominant enzyme products Main distribution

ALOX15 15-LOX-1 15(S)-HPETE, 15(S)-HETE Reticulocyte, , bronchial epithelial cells 15-LOX-2 15(S)-HPETE, 15(S)-HETE Prostate, skin, lung, cornea ALOX12 -type lipoxygenase 12 12(S)-HPETE, 12(S)-HETE In various cell types Epidermis-type lipoxygenase 12 12(R)-HPETE, 12(R)-HETE In various cell types Leukocyte-type lipoxygenase 12 12(S)-HPETE, 12(S)-HETE In various cell types ALOX8 8-LOX 8(S)-HPETE, 8(S)-HETE Only in mice and rats tissues ALOX5 5-LOX 5-HETE, In various cell types

123 J Physiol Sci (2012) 62:163–172 165

15-hydroxyeicosatetraenoic acid (15-HETE), but they share 15-HETE inhibits the activity of 5-LO and LT production only 40% amino acid homology, and there are two major by [32–34]. The expression of 15-LO induced differences between the . The first difference is by interleukin (IL)-4 in significantly decreased that 15-LO-1 converts AA to 15(S)-HPETE (90%) and the LTB4 expression [35]. 15-HETE can inhibit lesser amounts of 12(S)-HPETE (10%), whereas 15-LO-2 migration across -activated (interleukin-1 beta or produces exclusively 15(S)-HPETE [17]. The second dif- tumor necrosis factor-alpha) endothelium [36]. Transfec- ference is that, although both arachidonic acid and linoleic tion of rat kidney with human 15-LO can suppress acid are preferred substrates for 15-LO-1, only arachidonic inflammation [37]. According to these studies, the in vivo acid is a substrate for 15-LO-2 [19, 20]. activity of 15-LO/15-HETE may be regarded as a protec- The human 5-LO consists of 673 amino acids and a non- tive response to limit or reverse inflammatory symptoms heme iron, and the sequence is highly homologous with and to maintain basic cell function [38]. those of other mammalian LOs and soybean 15-LO [21]. Also, it has been found that 15-LO is implicated in 5-LO catalyzes conversion of arachidonic acid to leukotri- the maturation of rabbit reticulocytes by inhibiting ene (LT) A4, which can be subsequently converted into the mitochondria degradation [39–41]. 15-HETE improves the potent chemoattractant LTB4, or into cysteinyl leukotrienes proliferation of Friend erythroleukemia cells, rat aortic (Cys-LTs: LTC4, LTD4, and LTE4) [22]. 8-LO is consisted smooth muscle cells, and calf PASMCs [42–44], and even of 677 amino acids, which displays 78% sequence identity plays an important role in differentiation and function of to human 15-LO-2 considered to be its human orthologue. [45]. Moreover, 15-LO plays a role in pro- and 8-LO expression or activity has only been detected in tis- anti-carcinogenesis [46–48], 15-HETE also triggers cell sues of mice and rats [7, 8, 23], and is predominantly death through the release of cytochrome C, activation of expressed in epithelia of mice, hair follicle, forestomach, caspase-3, and PARP-1 (poly (ADP) ribose polymerase-1) and footsole. 8-HETE is a major arachidonic acid metabo- cleavage in the K-562 cell line [49]. Chronic inflammation lite for 8-LO [24]. There are three isoforms of 12-LO named plays an important role in atherogenesis. Furthermore, there after the cells where they were first identified; platelet, is evidence for a pro-atherosclerotic effect and anti-athero- leukocyte, and epidermis. The leukocyte-type enzyme is sclerotic effect of 15-LO [50–52]. widely distributed among cells, but the tissue distribution Although 15-LO/15-HETE participates in various phys- varies substantially from species to species. The platelet and iological and pathological processes, yet the exact role and epidermal enzymes are present in only a relatively limited mechanism in HPH have not been explained, so here we will number of cell types, but murine epidermis-type 12-LOX is describe in detail the effect of 15-LO/15-HETE on hypoxic not a functional human gene [9]. The 12-LO pathway pulmonary vasoconstriction and vascular remodeling. metabolizes AA to a variety of products with numerous biological activities, and the major products of this pathway are 12(S)-HETE, hydroxyepoxy-containing , and 15-LO/15-HETE and HPH trihydroxy-containing trioxilins [25]. Distribution and expression of 15-LO/15-HETE in HPH

Biological role of 15-LO/15-HETE It is reported that only 15-LO-1 is expressed in normoxic lung tissues, and that 15-LO-1 and 15-LO-2 are upregu- 15-LOs are peroxidizing enzymes that catalyze the lated by hypoxia. Moreover, in hypoxic , 15-LO is stereoselective introduction of molecular dioxygen at car- concentrated in the microsomes, whereas in normoxic bon 15 (C-15) of arachidonic acid [26, 27], and their lungs, 15-LO is localized in the cytosol, suggesting that expression and arachidonic acid metabolites are implicated activation of 15-LO is associated with translocation of the in several important inflammatory conditions, cell differ- enzyme from the cytosol to membrane under hypoxic entiation, carcinogenesis, atherogenesis, and other potential conditions [53]. Moreover, the 15-LO-1 mRNA and functions. The physiologic roles of the enzymes and ara- were localized in pulmonary artery endothelial cells chidonic acid metabolites are dependent on the context in (PAECs), while the 15-LO-2 mRNA and protein were which (tissue- and species-specificity) they are expressed. localized in both PAECs and pulmonary smooth muscle Tissue levels of 15-LOs and 15-HETE are often elevated cells (PASMCs) [54]. Furthermore, both 15-LO-1 and during inflammation condition. Further evidence for a role 15-LO-2 were up-regulated and localized in PASMCs and of 15-HETE is that it is increased in and chronic PAECs of pulmonary vessels from patients displaying bronchitis patients and animals [28–31]. Several lines of severe PH [44]. Using a combination of high-pressure ex vivo studies have documented that 15-LOs product liquid chromatography (HPLC) and gas chromatography/ 15-HETE might have anti-inflammatory properties. mass spectrometry (GC/MS), the synthesis of 15-HETE 123 166 J Physiol Sci (2012) 62:163–172 was increased in microsomes from hypoxic lungs and this depolarization, opens VDCCs, promotes Ca2? influx, 2? effect is dependent on the lipoxygenase pathway [53]. increases [Ca ]i, and triggers PASMCs contraction. Studies have suggested that K? channels in PASMCs are 15-LO/15-HETE and hypoxic pulmonary inhibited by subacute hypoxia, leading to depolarization, 2? vasoconstriction an increase in [Ca ]i, and constriction of pulmonary arteries [59, 60]. These K? channels are voltage-gated and 15-HETE increases intracellular Ca2? and contracts sensitive to 4-aminopyridine (4-AP) [61–63]. However, pulmonary arteries how the K? channels are inhibited after subacute hypoxia remains elusive. Both direct and indirect effects have been 15-HETE increases the tension of PA from hypoxic rats in a proposed for the channel inhibition. concentration-dependent manner [53]. After inhibiting the Our studies have shown that inhibiting KATP and BKCa endogenous production of 15-HETE, the reaction of hypoxic channels could not affect 15-HETE induced vasoconstric- pulmonary artery rings to phenylephrine (a vasoconstrictor tion, but once inhibited Kv channels can completely block and used to detect the viability of vessels) was markedly the effect of 15-HETE on pulmonary arteries [64], decreased, suggesting that endogenous 15-HETE is involved 15-HETE can inhibit the Kv currents of PASMCs [65]. in pulmonary vasoconstriction. PA vasoconstriction induced Recent studies also identified that subacute hypoxia down- by 15-HETE is triggered by an increase in intracellular Ca2? regulates Kv1.5, Kv2.1, and Kv3.4 channel expression and 2? concentration([Ca ]i) in PASMCs, which is in turn caused suppresses IK current through endogenous 15-HETE. by Ca2? release from intracellular Ca2? stores, or an influx 15-HETE was found to be more potent than 5-HETE and of Ca2? through ion channels such as L-type and store- 12-HETE in mediating hypoxia-induced down-regulation operated calcium channels (SOCCs) [55]. of Kv3.4 channel expression. These results fill the lacunae More and more studies are showing that there is an which define how subacute hypoxia inhibits Kv channels important role for SOCCs in the chronic hypoxia-induced leading to membrane depolarization and an increase in 2? 2? increase in resting [Ca ]i which is responsible for HPV but [Ca ]i level in PASMCs, and demonstrate the link eliminates a role for voltage-dependent calcium channels between 15-LO, 15-HETE formation, and pulmonary (VDCCs) during this procedure [56]. Our data also show that vasoconstriction after subacute hypoxia [66–68]. transient potential channel 1 (TRPC1), one candi- date of SOCCs, was up-regulated by 15-HETE, leading to Effects of pulmonary artery endothelial cells on 15-HETE elevation of capacitative calcium entry (CCE) via SOCCs in induced pulmonary vasoconstriction PASMCs [57]. It has been suggested that the mechanism of 2? 2? 15-HETE mobilizes [Ca ]i signaling through Ca release PAECs can release several kinds of vascular activity fac- 2? from intracellular Ca stores via IP3 receptor- and ryano- tors such as PGE2, NO, and some others, which have dine receptor-operated Ca2? channels. After depletion of important contributions to vasoconstriction. Hypoxia sarcoplasmic reticulum Ca2? stores, the resulting Ca2? reduces the activity of eNOS to decrease the production of influx, known as CCE, is mediated by SOCCs, and consists NO, then contracts PAs [69]. In in vitro tension studies, of up-regulated TRPC1. The other mechanism is directly denuded endothelial and inhibiting the NO production of activating Ca2? entry from extracellular solution via L-type vascular rings increased the effect of 15-HETE on PAs Ca2? channels (VDCCs). PASMCs are required to maintain contraction. Blockage of endogenous 15-HETE can induce 2? active vascular tones, then the increased [Ca ]i can form the production of NO in PAECs. Moreover, 15-HETE complexes with calmodulin, which activates myosin light phosphorylated eNOS at Thr495, causing reduced activity chain (MLC) kinase (MLCK), causing phosphorylation of of eNOS [70]. In addition, the immunoprecipitation (IP) MLC. Phosphorylated MLC (P-MLC) then facilitates stim- supported there were 15-LO, Hsp90, and Akt in an eNOS ulation of myosin ATPase activity by actin leading to cross- complex in PAECs, and therefore these data must be bridge cycling and contraction [58]. interpreted with 15-HETE overcoming the protein network of eNOS process through phosphorylating or de-phos- 15-HETE induces pulmonary vasoconstriction phorylating to inactivate some sites of eNOS resulting in by inhibiting Kv channels reduced NO, thereby contracting PAs.

The resting membrane potential (Em) is primarily deter- 15-HETE regulates pulmonary vessels rhythm by protein mined by K? permeability and K? concentration gradient kinase pathways across the plasma membrane, and therefore the activity of K? channels in the plasma membrane is a critical deter- Protein kinase pathways play an important role in HPV, ? minant of Em. Inhibition of K channels causes membrane such as PKC, Rho kinase, Rho-associated serine/threonine 123 J Physiol Sci (2012) 62:163–172 167 kinase (ROCK), and extracellular signal-regulated kinase related to tissue homeostasis, when this balance is disrupted, 1/2 (ERK1/2). Tension measurements of responsiveness of diseases such as PAH can result [75]. The enhanced VSMC rat PA rings have demonstrated that incubation with specific proliferation and suppressed normal VSMC apoptosis are protein kinase inhibitors significantly attenuated the con- likely the major reasons leading to medial hypertrophy, striction of PA rings to 15-HETE under hypoxic condi- arterial remodeling, and vascular lumen narrowing [76]. tions. 15-HETE can activate the translocation of PKC Indeed, the inadequate apoptosis has been implicated in the isoforms, PKC-delta and PKC-varepsilon, from the cyto- development and maintenance of severe pulmonary hyper- plasm to the membranes of PASMCs, then down-regulate tension. We found subtle thickening of proximal media/ expression of Kv1.5, Kv2.1, and Kv3.4 channels to protect adventitia of the PA in rats exposed to hypoxia, which was the effect of 15-HETE on PAs [71]. Also, 15-HETE med- associated with an up-regulation of the anti-apoptotic Bcl-2 iated the up-regulation of ROCK expression and promoted expression and down-regulation of activated caspase-3 and the translocation of ROCK2 from the nucleus to the cyto- Bax expression in PA homogenates [54]. plasm through G-protein and tyrosine kinase pathways The effects of hypoxia on PASMCs apoptosis are well under hypoxic conditions, then leading to PA vasocon- known; however, whether 15-HETE acts on the apoptotic striction [72]. Furthermore, the ERK1/2 pathway was responses in PASMCs remains unclear. Studies have involved in 15-HETE-induced PA vasoconstriction, the shown that 15-HETE induced anti-apoptotic Bcl-2 ERK1/2 phosphorylation was also upregulated by 15-HETE expression, and down-regulated apoptotic caspase-3, Bax, in a dose-dependent manner, and this phosphorylation was FasL, Bad and caspase-9 expression to prevent PASMCs detected in cytosol as well as in nucleus [73]. These data from apoptosis via ROCK, HSP90, PI3K/Akt, ERK1/2, and shown above suggested that 15-HETE mediated HPV by iNOS pathways. Some methods such as cell viability activating different signal transduction pathways. measurement, nuclear morphology determination, TUNEL assay, and mitochondrial potential analysis have also 15-LO/15-HETE and HPVR demonstrated that 15-HETE suppressed PASMC apoptosis and improved cell survival, contributing to HPVR includ- Hypoxia induces pathological changes of the pulmonary ing morphological alterations, mitochondrial depolariza- vasculature mainly including: extracellular matrix compo- tion, and the expression of anti-apoptotic [77–80]. nents such as increase in collagen fibers and elastic fibers, Activity of Kv channels also plays a major role in reg- smooth muscle cell hypertrophy and hyperplasia, endo- ulating the PASMCs population in the pulmonary vascu- thelial cell swelling, hypertrophy, thereby resulting in lature, as they are involved in cell apoptosis, survival, and pulmonary tube wall thickening, and luminal stenosis, proliferation [3, 75, 76]. PASMCs from PAH patients reducing blood vessel flexibility in the vessel wall cavity demonstrate many cellular abnormalities linked to Kv volume level. Under conditions of prolonged hypoxia, channels, including decreased Kv current, down-regulated although recovering the PO2 to normoxic conditions, the expression of various Kv channels, and inhibited apoptosis pulmonary artery pressure is still higher than normal val- [81, 82]. It is well known that hypoxia can inhibit Kv ues. It can be concluded that hypoxic pulmonary vascular channels, inhibiting cell apoptosis, but it remains unclear remodeling (HPVR) is the main mechanism of HPH [74]. whether K? channels participate in the 15-HETE anti- It has been reported that PA remodeling induced by apoptotic process under hypoxic conditions. Data have also hypoxia in vivo is mediated by the 15-LO/15-HETE shown that 15-HETE enhanced cell survival, suppressed pathway at least in part. Moreover, both 15-LO-1 and the expression and activity of caspase-3, up-regulated Bcl- 15-LO-2 were overexpressed in the pulmonary vessels of 2 and attenuated mitochondrial depolarization, prevented human PH lungs and localized in PASMCs and PAECs chromatin condensation, and partly reversed K? channel from pulmonary vessels of patients displaying severe PH opener-induced apoptosis in PASMCs under serum- [44]. Intragastric administration of rats with 15-LO inhib- deprived conditions, indicating that 15-HETE inhibited the itor (nordihydroguaiaretic acid, NDGA) under hypoxic apoptosis in PASMCs through, at least in part, inactivating conditions decreased the formation of the endogenous K? channels [83]. 15-HETE level, which also reversed all the pathological changes of PAs induced by hypoxia, including the depo- 15-HETE and PASMCs proliferation sition of collagen and medial thickening [44, 54]. Studies on the exact mechanism of 15-HETE on HPVR are 15-HETE and PASMCs apoptosis currently in progress. Until now, it has been found that proliferating cell nuclear antigen (PCNA) and Cyclin A Especially considering the fact that maintaining the proper were up-regulated by endogenous 15-HETE induced by balance between cell apoptosis and proliferation is closely hypoxia and exogenous 15-HETE in PASMCs, and that the 123 168 J Physiol Sci (2012) 62:163–172 effect was also abolished in the presence of cinnamyl- a structural adaptation that have important beneficial 3,4-dihydroxy-a-cyanocinnamate (CDC), the inhibitor of results for gas exchange, has recently been reported [86]. 15-LO. Moreover, hypoxia and exogenous 15-HETE sig- The specific vascular endothelial mitogen, the vascular nificantly enhanced 5-bromodeoxyuridine (BrdU) incor- endothelial (VEGF) family, plays an poration and microtubule formation by a-tubulin, and made important role in the development of PH, and chronic more PASMCs accumulation at the G2/M?S phase, hypoxia can lead to increased VEGF, PIGF, and their respectively. CDC also suppressed the cell proliferation, receptor expression in the lung [87, 88]. The ROCK a-tubulin polymerizatio,n and made more PASMCs arrest pathway also mediates hypoxia-induced capillary angio- at the G0/G1 phase of the cell cycle. Our results also genesis [89]. However, the mechanism by which hypoxia clarified that the ROCK pathway was responsible for induced the angiogenesis in PH needs to be explored 15-HETE-induced PASMCs proliferation, which contrib- further. uted to media hypertrophy. These findings appeared in Our study also showed that hypoxia could induce angi- favor of the potential relevance of ROCK pathway and ogenesis, and that this effect can be inhibited by intragastric 15-HETE inhibition in the treatment of human PH [44]. administration of NDGA in vivo in rats, indicating that endogenous 15-HETE was involved in hypoxia-induced 15-HETE and angiogenesis angiogenesis. It has also been found that exogenous 15-HETE can induce bovine PAECs migration, tube for- Most studies conclude that the structural changes that are mation in Matrigel, or vessel density in chick chorioallan- thought to underlie the increased vascular resistance can be toic membrane under normoxic conditions [44]. broadly classified into two processes: firstly, remodeling of Meanwhile, hypoxia induced significant PAECs migration the walls of the pulmonary resistance vessels, and, sec- and tube formation was blocked by CDC. However, the ondly, a reduction in the total number of blood vessels in inhibitory effect was partly diminished in the presence of the lung [74, 84]. The second major structural alteration exogenous 15-HETE [44], and also ROCK pathway medi- caused by chronic hypoxia is loss of small blood vessels, ated the effect of 15-HETE-induced PAECs migration, tube sometimes termed rarefaction or pruning, which is said to formation in vitro, and chick chorioallantoic membrane increase vascular resistance by reducing the extent of angiogenesis in vivo. These results indicated that 15-HETE parallel vascular pathways [85]. But some other researchers was a potent mediator involved in hypoxia-induced pul- question this widely accepted paradigm, and hypoxia- monary vascular angiogenesis. Also, we are studying induced angiogenesis in the mature pulmonary circulation, whether 15-HETE could regulate other pathways to

Fig. 1 Role of 15-LO/15- HETE in hypoxia-induced pulmonary hypertension. Hypoxia-induced 15-LO/15- HETE function and expression stimulates pulmonary arteries constriction, promotes pulmonary artery endothelial cell (PAEC) and smooth muscle cell (PASMC) proliferation and inhibits PASMC apoptosis. The increased vascular pressure, proliferation and inhibited apoptosis in PASMC may play an important role in initiation and/or progression of pulmonary vascular remodeling

123 J Physiol Sci (2012) 62:163–172 169 promote angiogenesis, such as VEGF and PIGF. From all an important mechanism underlying the treatment of PAH the results, we can conclude 15-LO/15-HETE plays an and provide a novel therapeutic in sight for the future. important role in HPH as in Fig. 1. Although 15-LO/15-HETE exerted an integral role in the development of pulmonary hypertension, the mechanism by which 15-LO was regulated under hypoxic conditions is 5-LO/12-LO and PH still not clear. So further studies will need to evaluate the precise mechanism of hypoxia-?regulated 15-LO expres- In addition to the 15-LO pathway, many other data suggest sion and activity. that arachidonic acid via 5-LO and 12-LO also play pivotal roles in PH, since in one of these studies, 5-LO Acknowledgments This work was supported by National Natural expression was unregulated in PAECs from patients with Science Foundation of China (Nos. 30370578, 30470752 and 31071007), Science Foundation of Education Department of PAH [90], in rats subjected to chronic hypoxia [91], and in Heilongjiang Provence (Nos. 11531181 and 11551275) and Science mice challenged with antigen [92]. Cys-LTs was also found Foundation of Health Department of Heilongjiang Provence (Nos. to be in the lung lavage fluid of neonates with persistent 2009-250 and 2009-251). 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